| First Author | Gregg T | Year | 2019 |
| Journal | J Biol Chem | Volume | 294 |
| Issue | 12 | Pages | 4656-4666 |
| PubMed ID | 30700550 | Mgi Jnum | J:276646 |
| Mgi Id | MGI:6307529 | Doi | 10.1074/jbc.RA118.006085 |
| Citation | Gregg T, et al. (2019) Obesity-dependent CDK1 signaling stimulates mitochondrial respiration at complex I in pancreatic beta-cells. J Biol Chem 294(12):4656-4666 |
| abstractText | beta-Cell mitochondria play a central role in coupling glucose metabolism with insulin secretion. Here, we identified a metabolic function of cyclin-dependent kinase 1 (CDK1)/cyclin B1-the activation of mitochondrial respiratory complex I-that is active in quiescent adult beta-cells and hyperactive in beta-cells from obese (ob/ob) mice. In WT islets, respirometry revealed that 65% of complex I flux and 49% of state 3 respiration is sensitive to CDK1 inhibition. Islets from ob/ob mice expressed more cyclin B1 and exhibited a higher sensitivity to CDK1 blockade, which reduced complex I flux by 76% and state 3 respiration by 79%. The ensuing reduction in mitochondrial NADH utilization, measured with two-photon NAD(P)H fluorescence lifetime imaging (FLIM), was matched in the cytosol by a lag in citrate cycling, as shown with a FRET reporter targeted to beta-cells. Moreover, time-resolved measurements revealed that in ob/ob islets, where complex I flux dominates respiration, CDK1 inhibition is sufficient to restrict the duty cycle of ATP/ADP and calcium oscillations, the parameter that dynamically encodes beta-cell glucose sensing. Direct complex I inhibition with rotenone mimicked the restrictive effects of CDK1 inhibition on mitochondrial respiration, NADH turnover, ATP/ADP, and calcium influx. These findings identify complex I as a critical mediator of obesity-associated metabolic remodeling in beta-cells and implicate CDK1 as a regulator of complex I that enhances beta-cell glucose sensing. |
